NORTHERA (DROXIDOPA) for Dysautonomia in Adult Survivors of Menkes Disease and Occipital Horn Syndrome

Phase I/II Study of NORTHERA (DROXIDOPA) for Dysautonomia in Adult Survivors of Menkes Disease and Adults With Occipital Horn Syndrome: Double-blind Placebo-controlled Randomized Crossover Clinical Trial

The purpose of this study is to evaluate whether Northera (Droxidopa) is safe and effective in young adults with Menkes disease who survived the most severe complications of their illness or adults with occipital horn syndrome (OHS), who have trouble with intermittent low blood pressure and other symptoms of dysautonomia. The outcomes and information from this study may help adult survivors of Menkes disease and individuals with OHS lead more normal day-to-day lives.

Study Overview

• Status: Recruiting
• Conditions: Menkes Disease; Occipital Horn Syndrome
• Intervention / Treatment: Drug: Droxidopa; Other: Placebo

Detailed Description

This pilot clinical trial will evaluate the safety, tolerability, dosing, and preliminary efficacy of Northera (Droxidopa) treatment in young adults who survived the major neurodegenerative and neurocognitive effects of Menkes disease through early Copper Histidinate treatment. We hypothesize that Northera (Droxidopa) in Menkes disease survivors with symptoms of dysautonomia (e.g., syncope, dizziness, orthostatic hypotension, abnormal sinoatrial conduction, nocturnal bradycardia, and bowel or bladder dysfunction) from persistent deficiency of the copper-dependent enzyme, dopamine-β-hydroxylase, will be safe, and correct or improve blood neurochemical levels, raise systolic blood pressure, and produce symptomatic improvement and better overall quality of life. We will test this hypothesis in six to ten Menkes disease survivors or OHS patients in a double-blind placebo-controlled randomized crossover clinical trial.

• Study Type: Interventional
• Enrollment (Anticipated): 6
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Stephen G. Kaler, MD; Phone Number: 614 722-5964; Email: stephen.kaler@nationwidechildrens.org

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Recruiting
      • Nationwide Children's Hospital
      • Contact: Stephen G Kaler, MD; Phone Number: 614-722-5964

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult persons with Menkes disease who survived beyond the expected natural history, attained independent ambulation, attend (or attended) school, and reached adulthood after early CuHis treatment for three years or adults with Occipital Horn Syndrome, who manifest clinical signs and symptoms of dysautonomia, e.g., orthostatic hypotension: specifically, a decrease in systolic or diastolic blood pressure of at least 20 or 10 mm Hg, respectively, within three minutes after standing, and/or chronic diarrhea: production of loose stools with or without increased stool frequency for more than four weeks immediately preceding enrollment.
2. History of at least thrice weekly occurrence of dizziness/feeling lightheaded while standing upright and/or thrice weekly episodes of diarrhea or an urgent need to defecate after food ingestion for more than four weeks immediately preceding enrollment.
3. Documented mutation in ATP7A.
4. Must sign and date an Informed Consent Form (ICF).
5. Age ≥ 18 years of age.
6. Ability to adhere to the prescribed oral Northera (Droxidopa) regimen.
7. Willingness to comply with all study visits and procedures.

Exclusion Criteria:

1. Pre-existing liver (e.g., hepatitis, biliary atresia, cirrhosis) or kidney disease (i.e., calculated glomerular filtration rate <30 ml/min).
2. History of hypertension, anti-hypertensive therapy, heart failure (or decreased ejection fraction), cardiac arrhythmia, or bleeding diatheses.
3. Any disease or condition that, in the opinion of the Investigator, has a high probability of precluding the subject from completing the study or where the subject cannot or will not appropriately comply with study requirements.
4. Any alpha-1 adrenoreceptor agonist, beta-blocker, DOPA decarboxylase inhibitor, midodrine, ephedrine, or any triptan medication as a concomitant medication.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Northera™ (Droxidopa) (Treatment A); Northera (Droxidopa) (Treatment A) will be provided to adult subjects as a capsule with 100mg, 200mg, or 300mg of Northera (Droxidopa) contained within gelatin color capsules (sky blue and white, size 0) based on findings from the dose titration visit. These capsules are physically indistinguishable from the Treatment B (placebo) capsules. Frequency of administration (by mouth) will be twice daily for six weeks.	Drug: Droxidopa; Subjects will self-administer capsules of Droxidopa by mouth twice daily for six weeks.; Other Names: Northera
Placebo Comparator: Placebo (Treatment B); Empty gelatin color capsules (sky blue and white, size 0) filled with cellulose microcrystalline and physically indistinguishable from Treatment A capsules. Frequency of administration (by mouth) will be twice daily for six weeks	Other: Placebo; Subjects will self-administer capsules of placebo by mouth twice daily for six weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5 tool	Grade 1-5 with increasing severity from 1 to 5	Six week periods of Active drug versus Placebo

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in plasma catechol levels after Northera (Droxidopa)	Serial determinations of norepinephrine and dihydroxyphenylglycol	Six week periods of active drug versus placebo
Changes in systolic blood pressure after Northera (Droxidopa)	Serial BP measurements including at-home monitoring	Six week periods of active drug versus placebo
Changes in gastrointestinal symptoms after Northera (Droxidopa)	As reflected in the Irritable Bowel Syndrome-Diarrhea report	Six week periods of active drug versus placebo
Changes in Time standing duration after Northera (Droxidopa)	Measured in time seconds	Six week periods of active drug versus placebo
Changes in Up and Go test performance after Northera (Droxidopa)	Measured in time (seconds) needed to stand up from a chair, walk 3 m and return to a seated position on the chair.	Six week periods of active drug versus placebo
Changes in 6 minute walk test performance after Northera (Droxidopa)	Measured in distance (meters) walked in 6 minutes	Six week periods of active drug versus placebo

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in scores on the Orthostatic Hypotension Symptom Assessment questionnaire after Northera (Droxidopa)	Scores range from zero to 10 with 0 meaning no symptoms and 10 meaning the worst possible symptoms	Six week periods of active drug versus placebo

Collaborators and Investigators

• Sponsor: Stephen G. Kaler, MD
• Investigators: Principal Investigator: Stephen G Kaler, MD, Nationwide Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2021
• Primary Completion (Anticipated): June 30, 2025
• Study Completion (Anticipated): June 30, 2026

Study Registration Dates

• First Submitted: July 9, 2021
• First Submitted That Met QC Criteria: July 22, 2021
• First Posted (Actual): July 26, 2021

Study Record Updates

• Last Update Posted (Estimate): January 10, 2023
• Last Update Submitted That Met QC Criteria: January 7, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Dysautonomia
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Congenital Abnormalities; Hematologic Diseases; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Connective Tissue Diseases; Hemostatic Disorders; Skin Diseases, Genetic; Metabolism, Inborn Errors; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Skin Abnormalities; Metal Metabolism, Inborn Errors; Hair Diseases; Collagen Diseases; Syndrome; Cutis Laxa; Primary Dysautonomias; Autonomic Nervous System Diseases; Ehlers-Danlos Syndrome; Menkes Kinky Hair Syndrome; Antiparkinson Agents; Anti-Dyskinesia Agents; Droxidopa
• Other Study ID Numbers: 00001113

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No